Transgenic expression of PML/RARα impairs myelopoiesis Journal Article
| Authors: | Early, E.; Moore, M. A. S.; Kakizuka, A.; Nason-Burchenal, K.; Martin, P.; Evans, R. M.; Dmitrovsky, E. |
| Article Title: | Transgenic expression of PML/RARα impairs myelopoiesis |
| Abstract: | The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor (RARα) on chromosome 17. This yields a fusion transcript, PML/RARα, a transcription factor with reported dominant negative functions in the absence of hormone. Clinical remissions induced with all-trans retinoic acid (RA) treatment in acute promyelocytic leukemia are linked to PML/RARα expression in leukemic cells. To evaluate the PML/RARα role in myelopoiesis, transgenic mice expressing PML/RARα were engineered. A full- length PML/RARα cDNA driven by the CD11b promoter was expressed in transgenic mice. Expression was confirmed in the bone marrow with a reverse transcription PCR assay. Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RARα transgenic and control mice. Cell sorter analysis of CD11b+ bone marrow cells revealed similar CD11b+ populations in transgenic and control mice. However, in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors, especially in those responding to granulocyte/macrophage colony-stimulating factor. Granulocyte/macrophage colony-stimulating factor and kit ligand cotreatment did not overcome this inhibition. Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation. Following irradiation, PML/RARα transgenic mice, as compared with controls, more rapidly depressed peripheral white blood cell and granulocyte counts. As expected, nearly all control mice (94.4%) survived irradiation, yet this irradiation was lethal to 45.8% of PML/RARα transgenic mice. Lethality was associated with more severe leukopenia in transgenic versus control mice. Retinoic acid treatment of irradiated PML/RARα mice enhanced granulocyte recovery. These data suggest that abnormal myelopoiesis due to PML/RARα expression is an early event in oncogenic transformation. |
| Keywords: | controlled study; gene translocation; nonhuman; polymerase chain reaction; animal cell; animals; mice; bone marrow cells; cells, cultured; stem cell factor; gene expression; erythropoietin; leukopenia; granulocyte macrophage colony stimulating factor; neoplasm proteins; animal experiment; animal model; transcription factor; transcription, genetic; transgenic mouse; animalia; mus musculus; mice, transgenic; transcription factors; nuclear proteins; leukemia, promyelocytic, acute; cytokines; dimethyl sulfoxide; gene rearrangement; rna, messenger; cd11b antigen; tumor suppressor proteins; irradiation; acute myeloblastic leukemia; transgene; hematopoietic stem cells; remission; translocation, genetic; leukocyte count; malignant transformation; granulocyte colony stimulating factor; retinoic acid; chromosome 17; lethality; colony stimulating factor 1; colony forming unit; chromosomes, human, pair 17; acute promyelocytic leukemia; chromosomes, human, pair 15; retinoic acid receptor; granulocyte-macrophage colony-stimulating factor; tretinoin; receptors, retinoic acid; all-trans retinoic acid; myelopoiesis; intraperitoneal drug administration; interleukin 3; granulocytes; chromosome 15; humans; male; female; priority journal; article |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 93 |
| Issue: | 15 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1996-07-23 |
| Start Page: | 7900 |
| End Page: | 7904 |
| Language: | English |
| DOI: | 10.1073/pnas.93.15.7900 |
| PUBMED: | 8755574 |
| PROVIDER: | scopus |
| PMCID: | PMC38846 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
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